In 1976, fermentation broths obtained from the soil bacteria Streptomyces cattleya were found to be active in screens for inhibitors of peptidoglycan biosynthesis. Initial attempts to isolate the active species proved difficult due to the chemical instability of that component. After many attempts and extensive purification, the material was finally isolated in >90% purity, allowing for the structural elucidation of the first isolated naturally-occurring carbapenem antibiotic, thienamycin. See, e.g., Kahan et al., J. Antibiot. (1979) 32:1-12.

Since 1978 to 2000, over twenty-three total chemical syntheses of thienamycin have been reported, the large majority producing thienamycin after 12 or more sequential chemical steps in relatively low yield (e.g., from 0.2% to 10% yield). See, e.g., Salzmann et al., J. Am. Chem. Soc. (1980) 102:6161; Huang et al., J. Am. Chem. Soc. (1980) 102:2060; Reider et al., Tetrahedron Letters (1982) 23:2293-2296; Desiraju et al., J. Chem. Soc. Chem. Comm. (1984) 494; Evans et al., Tetrahedron Letters (1986) 27:4961; Grieco et al., J. Am. Chem. Soc. (1984) 106:6414; and Jacobi et al., J. Org. Chem. (1996) 61:2413. Production of thienamycin through traditional fermentation from Streptomyces cattleya also faced significant hurdles, such as low titer and difficulties in isolating and purifying thienamycin produced by fermentation. See, e.g., U.S. Pat. Nos. 3,950,357 and 4,006,060 each of which are incorporated herein by reference. Thienamycin was eventually considered ill-suited for clinical treatment due to its chemical instability due in aqueous media and biological instability to dehydropeptidase-I (DHP-I). Researchers have since sought alternatives to thienamycin which maintain thienamycin's excellent antibacterial activity but are unfettered with thienamycin's stability problems.
One such carbapenem, imipenem, was developed in 1985 as an intravenous product. See, e.g., U.S. Pat. No. 4,194,047 incorporated herein by reference. Imipenem has a broad spectrum of activity against aerobic and anaerobic Gram positive as well as Gram negative bacteria, and continues to be commonly used against Pseudomonas aeruginosa, one of the leading agents of nosocomial infections. The current manufacture of imipenem utilizes a chemical synthetic route which is, from simple building blocks to the final product, typically low yielding, resulting in high levels of waste production and high cost of manufacture. See, e.g., Grabowski, Chirality (2005) 17:S249-S259, and references cited therein.

Other promising carbapenem antibiotics have been found efficacious in humans, e.g., including ertapenem (INVANZ, Merck), meropenem (MERREM, Astra Zeneca), panipenem, biapenem, doripenem (FINIBAX, Johnson & Johnson), L-646591, and ER-35768, each for parenteral use; orally active carbapenems CL-191121, L-036, DU-6681, and R-95867, and their corresponding ester prodrugs L-084, DZ-2640, and CS-834. See, e.g., Kumagai et al., Curr. Med. Chem.—Anti-Infective Agents (2002) 1:1-14. Other carbapenems include, but are not limited to, saftrinem, tebipenem, tomopenem, S-4661, SM 216601, GV 129606, ZD-4433, R-83201, BO-2502A, BO-3482, DK-35C, DA-1131, S-4661, L-786,392, L-695256, L-786,392, GV104326, GV-118819, GV 143253, MK-0826, J-110,441, J-111225, FR-21818, DX-8739, CS-023, ME-1036, CP 5068, CL 188624, CL-190294, OCA-983, T-5575, and PZ-60. The majority of these carbapenems are produced by chemical synthesis.

Thus there continues to remain a need for more efficient, environmentally friendly, and cost-effective processes for the production and development of existing and new carbapenems antibiotics.